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Relative binding energies predict crystallographic binding modes of ethionamide booster lead compounds

Lookup NU author(s): Dr Natalie TatumORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Transcriptional repressor EthR from Mycobacterium tuberculosis is a valuable target for antibiotic booster drugs. We previously reported a virtual screening campaign to identify EthR inhibitors for development. Two ligand binding orientations were often proposed, though only the top scoring pose was utilized for filtering of the large data set. We obtained biophysically validated hits, some of which yielded complex crystal structures. In some cases, the crystallized binding mode and top scoring mode agree, while for others an alternate ligand binding orientation was found. In this contribution, we combine rigid docking, molecular dynamics simulations, and the linear interaction energy method to calculate binding free energies and derive relative binding energies for a number of EthR inhibitors in both modes. This strategy allowed us to correctly predict the most favorable orientation. Therefore, this widely applicable approach will be suitable to triage multiple binding modes within EthR and other potential drug targets with similar characteristics.

Publication metadata

Author(s): Tatum NJ, Duarte F, Kamerlin SCL, Pohl E

Publication type: Article

Publication status: Published

Journal: Journal of Physical Chemistry Letters

Year: 2019

Volume: 10

Issue: 9

Pages: 2244-2249

Print publication date: 02/05/2019

Online publication date: 09/04/2019

Acceptance date: 09/04/2019

Date deposited: 22/07/2019

ISSN (electronic): 1948-7185

Publisher: American Chemical Society


DOI: 10.1021/acs.jpclett.9b00741


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Funder referenceFunder name
ASTF 123-2015